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In-vitro Delivery of Aerosolized Treprostinil via Modern Mechanical Ventilation

Rajeev Patel

Ann Cuccia

Gerald Smaldone

Paul Strachan


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Rajeev B. Patel, Ann D. Cuccia, Gerald C. Smaldone and Paul Strachan

Stony Brook University Medical Center, State University of New York, Stony Brook, NY, USA

BACKGROUNDAerosolized treprostinil, a prostacyclin vasodilator, is an approved therapy for patients with pulmonary arterial hypertension (PAH) and New York Heart Association functional class III symptoms. The approved delivery method, the Tyvaso Inhalation System, utilizes an interactive hand-held nebulizer designed for a cooperative spontaneously breathing patient. Our goal was to define a reliable method for delivering a standard dose of treprostinil, to an intubated patient maintained on mechanical ventilation.

METHODSAn AeroTech II jet nebulizer (CIS-US, Bedford, MA) was placed in the ventilator circuit with a test lung and run via an external continuous air flow at 10 L/min. Two ventilator types were compared, the Dräger Evita XL (Dräger Medical GmbH, Lübeck, Germany) and Avea (CareFusion, Yorba Linda, CA), each with controlled mechanical ventilation (CMV) and pressure control (PC), with and without humidity of 35°C and PEEP of 0-15 cm H2O. Aerosolized particles were radiolabeled by technetium-99m. Accuracy of radiolabel was confirmed by HPLC. Dose was defined by capturing particles exiting the endotracheal tube with a filter (Pari, Starnberg, Germany) and measuring radioactivity. Particle distributions were measured distal to the endotracheal tube by cascade impaction. The nebulizer was filled with radiolabeled treprostinil [1 ampule (1740 μg)]. Nebulizer output was defined by measuring captured aerosol (as a % of full Treprostinil ampule) from the device per minute until nebulizer dryness. Output was linear for 6 min. Data was represented by linear regression [y = 7.218x – 0.4043 (r2) 0.9991, p<0.0001 (x = time in min)]. Solving the equation where y equals the standard prescribed target dose of 54 μg (3.1% of full ampule), and x equals the time necessary to deliver the dose yields x = 0.483 min or 29 sec. We hypothesized that drug delivery would be determined by the number of breaths needed, such that the complete time of inspiration totaled 29 sec (e.g. number of breaths needed = 29 sec/TI, where TI is the inspiratory time of an average breath read from the ventilator display)

RESULTSHPLC confirmed that technetium-99m accurately represented the drug (y=1.032x – 1.496, (r2) 0.9895, p<0.0001). The mean inhaled dose ± SD was 61.08±7.71 μg (range 47.2 -84.4). By confidence intervals, there was no significant effect of ventilator type, mode, breathing pattern or PEEP. Humidity decreased drug delivery. Inspection of the data indicated that dosing increased proportionate to the number of breaths. This suggested that residual aerosol in the inspiratory line between breaths increased delivery. The mass median aerodynamic diameter and fine particle fraction were 0.70 μm & 0.99, respectively.

CONCLUSIONSFollowing a simple algorithm, it is possible to deliver aerosolized treprostinil, at controlled doses, to an intubated patient over a wide range of breathing patterns. For delivery comparable to the usual dose delivered by the Tyvaso Inhalation System, the conditions of nebulization must be precisely defined (full ampule of treprostinil per treatment, use of an AeroTech II, external flow at 10 L/min, bypass of the humidifier and treatment must be completed in 6 min or less).